This project will exploit mouse genetics to test the concepts and approaches that will be required to implement personalized medicine for human cancer. This will require joint studies, both within the mouse models of human cancer consortium (MMHCC) and together with other NCI-funded organizations, of systems genetics analysis of genetic background and gene expression networks in cancer susceptibility, progression and therapeutic responses. The value of systems-based approaches has been demonstrated from mouse studies of susceptibility to obesity and diabetes, in which the gene expression networks in normal tissues have revealed signaling pathways that reflect underlying susceptibility, as well as signaling hubs that are viable therapeutic targets. Similar studies of mouse models of skin cancer have identified hierarchical networks that control tissue structure and function, and provided novel insights into mechanisms that lead to skin tumor susceptibility. The application of these integrative systems approaches to cancer has major implications for all of the areas of research being pursued by the MMHCC. This project will include a Core Project, the purpose of which is to construct a browsable database of combined single nucleotide polymorphisms (SNPs) and gene expression data from tissues from interspecific backcross mice and from the Rl lines of the Collaborative Cross. Such a data base would be invaluable both for groups in the Cancer Susceptibility and Resistance cluster, but also more generally within the MMHCC and in other NCI-funded bodies. A tissue bank from the same animals will be available to members of the MMHCC for investigations of the genetic control of gene expression at the protein level. Pilot projects will be set up within the cancer susceptibility and resistance theme to use the same genetic approaches to investigate tumor susceptibility using different mouse models that represent the major forms of human cancer. A further goal is to investigate the interplay between germline polymorphisms and somatic events in cancer detection, progression and treatment responses. These aims overlap substantially with the Roadmap initiative, and in particular with the goals of the Integrated Cancer Biology Program (ICBP), the Specialized Programs of Research Excellence (SPORE) program, the Early Detection Research Network (EDRN) and the Cancer Family Registry (CFR). Representatives of each of these programs have provided supporting materials for this comparative mouse-human genetic approach to analysis of multiple aspects of cancer susceptibility.